Adenosine and Adenosine 5’-triphosphate Catabolism in Systemic Blood as a Potential Biomarker for Doxorubicin Cardiotoxicity in an Experimental Rat Model in vivo

Author(s):

Abstract:

Background: Previous studies have shown that metabolism of adenosine 5’-triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity.

Objective: To investigate the acute effect of high dose of doxorubicin (DOX) on adenosine and ATP catabolism in systemic blood in vivo.

Method: Sprague Dawley (SD) rats were each given either 10 mg/kg of DOX (n = 8) or normal saline (1 mL/kg, n = 11) twice daily for 4 doses by subcutaneous (sc) injection. Blood samples were collected sequentially for up to 6 hours for measuring circulating concentrations of ATP, adenosine and their metabolites. Hemodynmic recording was obtained continuously after the last injection. The difference in response between groups was considered significant at p < 0.05 (t-test).

Results: Diastolic blood pressure (DBP) was significantly lower in the DOX treated rats than in the control before the final injection (87 ± 12 vs. 104 ± 11 mmHg, p < 0.05). Blood pressure fell gradually after the last injection and the decrease was significantly greater in the DOX treated group (p < 0.05). Plasma concentration of adenosine was significantly lower in the DOX treated group. In contrast, plasma concentrations of uric acid and hypoxanthine, as well as Red Blood Cell (RBC) concentrations of AMP, were significantly higher (p < 0.05).

Conclusion: Acute cardiotoxicity induced by DOX may be measured by the increased breakdown of ATP to AMP in the RBC and also breakdown of adenosine to hypoxanthine and uric acid in plasma.

Keywords:

Adenosine, ATP, cardiotoxicity, doxorubicin, catabolism, rats.

Affiliation:

Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Pharmacokinetics and Metabolism Laboratory, College of Pharmacy and Department of Medicine, Faculties of Health Professions and Medicine, Dalhousie University, Halifax, NS, Biopharmaceutics and Drug Delivery Laboratory, College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax, NS